Shintani Takafumi, Ihara Masaru, Sakuta Hiraki, Takahashi Hiroo, Watakabe Ikuko, Noda Masaharu
Division of Molecular Neurobiology, National Institute for Basic Biology, 5-1 Higashiyama, Myodaiji-cho, Okazaki 444-8787, Japan.
Nat Neurosci. 2006 Jun;9(6):761-9. doi: 10.1038/nn1697. Epub 2006 May 7.
Eph receptors are activated by the autophosphorylation of tyrosine residues upon the binding of their ligands, the ephrins; however, the protein tyrosine phosphatases (PTPs) responsible for the negative regulation of Eph receptors have not been elucidated. Here, we identified protein tyrosine phosphatase receptor type O (Ptpro) as a specific PTP that efficiently dephosphorylates both EphA and EphB receptors as substrates. Biochemical analyses revealed that Ptpro dephosphorylates a phosphotyrosine residue conserved in the juxtamembrane region, which is required for the activation and signal transmission of Eph receptors. Ptpro thus seems to moderate the amount of maximal activation of Eph receptors. Using the chick retinotectal projection system, we show that Ptpro controls the sensitivity of retinal axons to ephrins and thereby has a crucial role in the establishment of topographic projections. Our findings explain the molecular mechanism that determines the threshold of the response of Eph receptors to ephrins in vivo.
Eph受体在与它们的配体（即ephrin）结合后，通过酪氨酸残基的自磷酸化而被激活；然而，负责对Eph受体进行负调控的蛋白酪氨酸磷酸酶（PTP）尚未阐明。在这里，我们鉴定出O型蛋白酪氨酸磷酸酶受体（Ptpro）是一种特异性的PTP，它能有效地将EphA和EphB受体作为底物进行去磷酸化。生化分析表明，Ptpro使近膜区域保守的磷酸酪氨酸残基去磷酸化，而该残基是Eph受体激活和信号传导所必需的。因此，Ptpro似乎可调节Eph受体的最大激活量。利用鸡视网膜顶盖投射系统，我们表明Ptpro控制视网膜轴突对ephrin的敏感性，从而在拓扑投射的建立中起关键作用。我们的研究结果解释了在体内决定Eph受体对ephrin反应阈值的分子机制。
